Population pharmacokinetic analysis for simultaneous determination of Bmax and KD in vivo by positron emission tomography

Purpose: Changes in GABA(A)-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABAA-receptor properties, characterized by B-max and K-D. Procedures: Following an injection of [C-11]FMZ (dose range: 1-2,000 mu g) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. Results: Application of this method in control rats resulted in estimates of B-max and K-D (14.5 +/- 3.7 ng/ml and 4.68 +/- 1.5 ng/ml, respectively). Conclusions: The proposed population PK model allowed for simultaneous estimation of B-max and K-D for a group of animals using single injection PET experiments per animal.